Omalizumab Transitions in Severe Asthma: Factors Influencing Switching Decisions and Timing for Optimal Response

Severe asthma is a complex condition that often requires systemic corticosteroid use to manage frequent exacerbations, even at maximum dosages [1]. Despite this, patients with severe asthma can find it challenging to control their symptoms [2].

In Europe, six biological therapies are available for the management of severe asthma: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab [3]. However, only four of them (omalizumab, mepolizumab, benralizumab, and dupilumab) are available in the Gulf region including Kuwait [4]. Omalizumab is the first biologic approved for treating severe allergic asthma associated with high total serum IgE [5], while the other biologics are used for severe eosinophilic asthma and severe uncontrolled asthma [6, 7]. Omalizumab works by inhibiting the interaction between human IgE and the high- and low-affinity receptors [8]. Numerous studies have demonstrated the effectiveness of omalizumab in improving different clinical parameters of severe asthma and providing better control of disease exacerbation and airflow obstruction [9‒11]. However, some patients have a poor response to omalizumab and require alternative biologic therapies [12, 13].

Currently, there are no clear guidelines for deciding on the most effective biologic alternative and the ideal switching time to result in the best response. Our study evaluated real-life cases of patients with severe asthma who were treated with omalizumab for several years and then switched to alternative biologics. We examined factors associated with this decision to switch and identified the best time to switch.

This study analyzed patients aged 18 and above who had a severe asthma diagnosis as per the criteria of the European Respiratory Society/American Thoracic Society [14] and had been deemed eligible for omalizumab therapy as their initial biologic at Al-Rashed Allergy Center in Kuwait from January 2010 to May 2022. The researchers acquired retrospective medical records for patients with approval from the Ethics Committee Board of the College of Medicine and Ministry of Health (project number 2018/935) and secured informed consent from all patients who met the inclusion criteria following the Declaration of Helsinki. Excluded from this study were patients with incomplete data records, those who started with biologics other than omalizumab as their initial biologic, and those on biologic therapies for less than 1 year before the start of this study.

Patient data were gathered from medical records and recorded in an Excel sheet. The information collected included basic demographic characteristics such as age, gender, BMI, comorbidities, ACT score, FEV1%, fractional exhaled nitric oxide, total serum IgE, and blood and sputum eosinophil levels. The time leading up to the decision to switch from omalizumab to another biologic was also recorded.

The endpoint of the study was switching decisions; hence, patients were divided into two groups: those who continued with omalizumab (non-switchers) and those who switched to another biologic. Furthermore, based on evaluating the patient’s criteria at the switching point, the outcome of patients regarding omalizumab treatment was classified into good responder, poor responder, and stop medication. Good response was defined as meeting the following criteria [15]: a reduction in asthma exacerbations of 50% or more compared to baseline, a 50% or more reduction in courses of oral corticosteroids (OCSs) compared to baseline, meaningful improvement in ACT score of three or more from baseline, and a mean change of post-bronchodilator FEV1% of 150 mL or more compared to baseline, and poor response referred to patients who were still uncontrolled clinically and functionally even after augmenting all treatment options. The switch to another biologic was based on the physician’s decision and the patient’s response in case of availability to access to other alternative biologics.

We used an Excel sheet to collect and code the information. We assessed the normality of the data with the Shapiro-Wilk test in SigmaPlot for Windows version 12.5.0.38 (Systat Software, Inc., UK, 2011) and calculated descriptive statistics in Minitab for Windows (Minitab Inc., 2013, Pennsylvania, USA) version 17.1.0.0. We used an independent t test or paired t test to compare two mean values and the χ² test to compare frequencies. Additionally, we conducted a logistic regression analysis to identify possible predictors of switching decisions. We used the receiver operating characteristic curve to determine the best time to switch to pledge a good response in patients with access to other biologics; an area under the curve greater than 0.6 was considered acceptable. All tests were two-sided, and a p value <0.05 was considered significant.

26/116 (22.4%) of our patients switched from omalizumab; 33 of the 116 patients had access to multiple biological treatments, but only 9 of these 33 patients changed from omalizumab to another available biologic (Table 1). The average age of those who switched was 43 (±12) years; half of them were female, and their frequency was significantly lower than those who did not switch (p = 0.05). Over one-third of switchers had smoking-related risks (34.6%) and childhood-onset disease (46.15%). Moreover, almost half of the cases (46.15%) were obese, with an average BMI (SD) of 30 (8) kg/m². Additionally, there were significantly associated comorbidities, such as chronic rhinosinusitis (CRS) and nasal polyps (NPs) (p = 0.01) for both, as well as ischemic heart disease (IHD) (p = 0.01). Furthermore, sputum eosinophils were significantly higher among the switcher group (p = 0.002), whereas FEV1% and ACT scores were significantly lower (p = 0.009 and 0.01).

The percentage of sputum eosinophils was a crucial factor in deciding to switch medications (Table 2). Every one percent increase in sputum eosinophils doubled the likelihood of switching, even in non-adjusted and adjusted models (OR = 1.91 and 1.51, respectively, p < 0.001 for both).

The use of omalizumab had a significant impact on controlling asthma symptoms, especially among non-switchers (Fig. 1); in the non-switcher group, the mean ACT at baseline was 13.59 ± 0.51 increasing to 19.29 ± 0.51 at switching point (p < 0.001). In the switcher group, the mean ACT at baseline was 10.91 ± 0.87 increasing to 16.33 ± 0.98 at switching point (p < 0.001). Additionally, considering airway obstruction in the non-switcher group, the mean FEV1% at baseline was 61.8 ± 1.9 increasing significantly to 74.5 ± 4 at switching point (p = 0.02). However, in the switcher group, the mean FEV1% at baseline was 51.3 ± 3.3 increasing in a nonsignificant manner to 58 ± 8.5 at switching point (p = 0.31) (Fig. 2). 95 of the 116 patients (81.9%) reported a good response to omalizumab treatment, with a higher frequency (90%) in the non-switcher group versus 53.85% among switchers (p < 0.001) (Table 3).

Furthermore, the mean (SD) duration of omalizumab therapy till the switching decision was 7 (2) years; patients who had access to other biological options had a significantly shorter mean period of omalizumab therapy till the switching decision, which was 4.9 ± 1.5 years compared to 8.9 ± 1.3 years for those who only had affordable omalizumab (p < 0.001, Fig. 3). Out of the 33 patients who had access to other biologics, those who had a good response to treatment showed a shorter time to switch from omalizumab to another biologic, 4.5 ± 1.5 years versus 6.8 ± 0.8 years (p = 0.001, Fig. 4). The optimal time to predict the likelihood of a good response was less than 5.5 years, with an area under the curve of 0.91 and p = 0.003 (Fig. 5). This cutoff point provided a sensitivity and specificity of approximately 89% and 100%, respectively (Table 4).

With the increasing availability of biological therapies for severe asthma, it is crucial to understand how a patient’s pheno-endotype can determine eligibility for these treatments. While switching between biologics may have an impact on various aspects of asthma control, there is currently a lack of real-life data on this topic. Our study reveals that 28.45% of severe asthma patients who started omalizumab as a first biologic had access to switch to another biologics, and only 9 of the 33 changed to another biologic. However, the total number of switchers was 26 of 116 (22.4%). A recent multicenter study indicates that 79% of patients continue with their initial biologic therapy [16], highlighting the importance of strict eligibility criteria and biomarker-guided selection processes in determining the appropriate biologic for each patient. However, it is worth noting that some patients may qualify for multiple biologics, and switching between them could lead to better outcomes.

Our study identified switchers as males with different associated comorbidities, such as IHD, CRS, or NP. They had a significantly higher sputum eosinophil percentage and lower ACT score and FEV1%. Matsumoto-Sasaki et al. [17] found that switchers were significantly younger and had characteristic eosinophilic rhinosinusitis, as well as aspirin-exacerbated respiratory disease with higher blood eosinophil levels. A recent review and analysis of randomized control trials compared the effectiveness of tezepelumab with other approved biologics for severe uncontrolled asthma treatment. The study found that tezepelumab, dupilumab, benralizumab, mepolizumab, reslizumab, and omalizumab had similar efficacy in reducing asthma exacerbation rates and the severity of exacerbations that led to hospitalization or emergency room visits [18]. Additionally, the study suggested that tezepelumab is effective in a broader range of patients with severe, uncontrolled asthma compared to other approved biologics. Furthermore, tezepelumab was effective in treating patients without an eosinophilic phenotype. Moreover, Menzies-Gow et al. [16] found that switchers had a significantly higher fractional exhaled nitric oxide, were on long-term oral steroids, and experienced more emergency visits, hospitalization, and mechanical ventilation. Both studies [16, 17] demonstrated the presence of CRS as an associated comorbidity, similar to our study. However, while we did not classify our patients according to eosinophilic and non-eosinophilic profiles, our data showed that NP was indeed associated with a switch.

Associated comorbidities with severe asthma could influence the clinical response and should be considered a stumbling block in the asthma control pathway. However, other biologics in CRS and NP treatment options enabled the decision to switch to a possibly successful opportunity for these patients [19].

For those who switch treatments, having a higher percentage of sputum eosinophils indicate more severe asthma, worse lung function, and a lower quality of life. To improve asthma control and decrease eosinophilic inflammation, switching to a different biologic therapy is often recommended. However, using sputum eosinophils as a follow-up response marker is still a topic of debate due to differences in collection techniques and measurement methods [20]. Despite this, they are a valuable indicator of poor lung function, inflammation, and the start of remodeling [21].

In a recent review, Scioscia et al. [22] have compiled research and real-life experiences on biologics for severe asthma and their switching patterns. The authors suggest that switching to a different biologic may be necessary if the current treatment is not providing satisfactory results. Patients who needed to switch because of poor control with a previous biologic therapy tended to have higher blood eosinophil counts and more exacerbations, despite taking OCSs. At the same time, the authors recommend that more research is needed to understand which patients would benefit from switching to other monoclonal antibodies due to overlapping eligibility criteria [22].

We also found that 90% of non-switchers had a good response to omalizumab, while only 53.85% of switchers did. These results indicate that various uncontrollable factors, such as airway remodeling, may impact switching. Switching omalizumab to mepolizumab was reported to yield better asthma symptom control, reduced exacerbation rates, and improved lung function [23]. Nevertheless, this study also found that some patients did not respond well to the switch and experienced worsening asthma control.

Timing is crucial when it comes to improving response rates. Based on our data, omalizumab had long been used as the only treatment option for severe asthma for a long time; it became significantly shorter when other biologics became available in our markets, it did not underestimate the efficacy of omalizumab, and hence, from the 33 patients who had access to alternative biologics, only 9 patients exhibited switching. Nevertheless, those who had a good response to treatment showed a shorter time to switch from omalizumab to another biologic. The optimal time to predict the likelihood of a good response was less than 5.5 years; this cutoff point provided a sensitivity and specificity of approximately 89% and 100%, respectively.

Pelaia et al. [24] investigated the effects of switching from omalizumab to benralizumab at different time points, including baseline, pre-switching, and 1 year after the switch. They concluded that benralizumab positively impacted symptom control, lung function, reduction in exacerbations per year, and blood eosinophil count. Another study also examined the benefits of switching to benralizumab in patients who did not respond well to their initial biologics. The study found that switching was particularly effective in atopic patients, improving asthma symptom control and lung function [1].

Research on switching biological drugs for severe asthma patients is limited, but some promising findings have emerged. One study found that reslizumab improved asthma control in individuals with severe eosinophilic asthma who did not respond well to omalizumab [25]. The OSMO study also demonstrated improved asthma control when patients switched from omalizumab to mepolizumab [26], further supported by real-world evidence [27]. Preliminary findings suggest that switching from mepolizumab to benralizumab can improve quality of life and reduce OCS doses in patients with poorly controlled asthma [28]. There are also case reports indicating long-term responsiveness to mepolizumab in patients who failed omalizumab and bronchial thermoplasty [29]. However, the optimal timing and criteria for switching between biological drugs still require further clarification in severe asthma management. Limited studies have suggested attempting withdrawal or switching after 12 months of biological therapy [30, 31].

The current study used real-world data to demonstrate how omalizumab affects asthma patients. It emphasized the importance of related health comorbidities such as CRS and NP, poor asthma symptom control, persistent airway obstruction, and sputum eosinophilia in deciding when to switch to other biologics if the other biological therapies were available. Achieving positive results with underlying airway remodeling is difficult, but deciding to switch early can increase the likelihood of success. However, the study was limited by its retrospective design and small sample size, so future longitudinal studies should be conducted to prevent bias.

When alternative biological therapy was available, patients with severe uncontrolled asthma are more likely to switch their biologic if they have comorbidities, high sputum eosinophil levels, and low lung function. This decision is linked to CRS, NPs, and IHD. However, the sputum eosinophil level was the crucial factor in determining the likelihood of omalizumab transition. The optimal time to predict the likelihood of a good response was less than 5.5 years of treatment to switch.

The protocol for this study was reviewed and approved by the Ethics Committee Board of the College of Medicine and Ministry of Health (project number 2018/935).

The authors have no conflicts of interest to declare.

None.

Mona Al-Ahmad and Asmaa Ali contributed equally to this study. Ahmed Maher worked on data collection. Asmaa Ali analyzed and interpreted the results and helped in writing the manuscript. Mona Al-Ahmad and Asmaa Ali were major contributors to writing the manuscript. All authors read and approved the final manuscript.

Mona Al-Ahmad and Asmaa Ali contributed equally to this work.

The data supporting the findings of this study are available from the corresponding author upon reasonable request.